Cerebral oxygenation during locomotion is modulated by respiration

Abstract

25In the brain, increased neural activity is correlated with an increase of cerebral blood flow and 26 increased tissue oxygenation. However, how cerebral oxygen dynamics are controlled in the 27 behaving animals remains unclear. Here, we investigated to what extent the cerebral oxygenation 28 varies during natural behaviors that change the whole-body homeostasis, specifically exercise. 29We measured oxygen levels in the cortex of awake, head-fixed mice during locomotion using 30 polarography, spectroscopy, and two-photon phosphorescence lifetime measurements of oxygen 31 sensors. We found that locomotion significantly and globally increases cerebral oxygenation, 32 specifically in areas involved in locomotion, as well as in the frontal cortex and the olfactory bulb. 33The oxygenation increase persisted when neural activity and functional hyperemia were blocked, 34 occurred both in the tissue and in arteries feeding the brain, and was tightly correlated with 35 respiration rate and the phase of respiration cycle. Thus, respiration provides a dynamic pathway 36 for modulating cerebral oxygenation. 3An adequate oxygen supply is critical for proper brain function 1 , and deficiencies in tissue oxygen 38 is a noted comorbidity in human diseases 2 and aging 3 . For these reasons, there has been a great 39 deal of interest in studying dynamics of cerebral oxygenation [4][5][6][7][8][9] . However, there is a gap in our 40 understanding of how behavior, such as natural exercises like locomotion, affects cerebral 41 oxygenation. In natural environments, animals and humans have evolved to spend a substantial 42 portion of their waking hours locomoting 10 . As exercise is known to have a positive effect on brain 43 health 11,12 , a better understanding of the basic brain physiology accompanying the behaviors can 44 give insight into how exercise can improve brain function. During movement, neuromodulator 45 release and neural activity in many brain regions is elevated [13][14][15][16][17][18][19][20] , and there is an increase in 46 cardiac output and respiratory rate. How these changes in local and systemic factors interact to 47 control cerebral oxygenation is a fundamental question in brain physiology but is not well 48 understood. Most cerebral oxygenation studies are performed in anesthetized animals 8,9,[21][22][23] (but 49 see 4 ), or non-invasively in humans. Anesthesia causes large disruptions of brain metabolism and 50 neural activity 24 , and non-invasive human studies are impeded by technical issues, making 51 accurate determination of any aspect of brain tissue oxygenation problematic. 52Here we investigated how and by what mechanisms voluntary exercise impacts brain 53 tissue oxygenation. We used intrinsic optical signal imaging 13,25 , electrophysiology, Clark-type 54 polarography 5,6,23 , and two-photon phosphorescent dye measurement 4,8,9 to elucidate how 55 vasodilation, neural activity, and systemic factors combine to generate changes in brain 56 oxygenation. All experiments were performed in awake mice ...

nNOS-expressing interneurons control basal and behaviorally evoked arterial dilation in somatosensory cortex of mice

“…During bouts of voluntary locomotion, neural activity increased substantially in the forelimb/hindlimb representation in somatosensory cortex, as measured by changes in multi-unit firing rate and power in the gamma-band of the LFP (Fig. 1 -Figure Supplement 1) (Huo et al, 2014;Zhang et al, 2019). These increases are driven primarily by cutaneous sensation rather than proprioception Woodward, 1981, 1982;Chapin and Lin, 1984).…”

Neurovascular coupling and bilateral connectivity during NREM and REM sleep

“…The intrinsic optical signal contains contributions from arteries, veins, and capillaries (Huo et al, 2015b(Huo et al, , 2015aZhang et al, 2019), so to better understand how arterioles changes contribute to the signal, we used two photon microscopy (Shih et al, 2012a) to image pial and penetrating arterioles (25 and 4 arterioles respectively from six mice) ( Fig. 3a).…”

Phasic oxygen dynamics underlies fast choline-sensitive biosensor signals in the brain of behaving rodents

“…Remarkably, the time-scale dependence of biosensor response amplitude and lag relative to exogenous O 2 qualitatively matched that of spontaneous profiles, suggesting that the same directionality happens in spontaneous conditions. Locomotion-related O 2 elevations in head-fixed mice have been recently shown to be modulated mainly by respiration rate (Zhang et al, 2019), whereas SWR-evoked O 2 peaks have been indirectly inferred by fMRI and likely result from neurovascular coupling (Ramirez-Villegas et al, 2015). Thus our study provides a link between the neurophysiological or systemic mechanisms that modulate brain O 2 levels and the response of ChOx-based biosensors in vivo.…”

“…To get insights into 6 this question, we analyzed an additional category of events, consisting of fast O 2 transients detected 7 outside the time-windows surrounding SWRs and peaks in locomotion. Under this condition, the 8 average rate of O 2 peaks occurrence was only 18% of the rate computed from total O 2 peaks ( Figure 9 S4A), emphasizing the strong modulatory effect of hemodynamics and respiration on O 2 , potentially evoked by SWRs and locomotion, respectively (Leithner and Royl, 2014;Ramirez-Villegas et al, 2015;Zhang et al, 2019). Remarkably, virtually all (>95%) of these events had an associated COA transient.…”